The kidney plays a primary role in the long term control of arterial pressure [159-161]. Thus any attempt at modeling the causes and effects of hypertension on cardiovascular system will require accounting for renal function. This project will develop two connected models (Figure 2.11) of renal function. A physiological model will simulate blood flow, transport, and epithelial cell metabolism; a gene-level, molecular model will simulate transcriptional, signaling, and biochemical mechanisms related specifically to superoxide in a single nephron segment, the medullary thick ascending limb (mTAL). The two models will be integrated through the regulation of medullary blood flow. The innovative approach of integrating physiological modeling with pathway-specific molecular modeling is expected to generate novel hypotheses regarding gene-disease relationships in several rat models.